1. Field of the Invention
The present invention relates to a combination of at least one hypnotic agent with at least one substituted bis aryl and heteroaryl compound. More specifically, the present invention relates to a combination containing at least one hypnotic agent with at least one compound selected from a series of dialkylamino, piperidinyl or piperazinyl substituted bis aryl and heteroaryl derivatives, which are selective serotonin, 5HT2A, antagonists. The combination of this invention is useful in the treatment of a variety of sleep disorders.
2. Description of the Art
Chronic insomnia among adults in the United States has been estimated to be present in ten percent of the adult population, and the annual cost for its treatment is estimated at $10.9 billion. JAMA 1997; 278:2170-2177 at 2170. Chronic insomniacs report elevated levels of stress, anxiety, depression and medical illnesses. The most common class of medications for treating insomnia are the benzodiazepines, but the adverse effect profile of benzodiazepines include daytime sedation, diminished motor coordination, and cognitive impairments. Furthermore, the National Institutes of Health Consensus conference on Sleeping Pills and Insomnia in 1984 have developed guidelines discouraging the use of such sedative-hypnotics beyond 4-6 weeks because of concerns raised over drug misuse, dependency, withdrawal and rebound insomnia. JAMA 1997; 278:2170-2177 at 2170. Therefore, it is desirable to have a pharmacological agent for the treatment of insomnia which is more effective and/or has fewer side effects than those currently used.
The prevalence of obstructive sleep apnea is estimated to be approximately 1-10% in the adult population, but may be higher in elderly individuals; Diagnostic and Statistical Manual of Mental Disorders 4th ed., American Psychiatric Association, Washington D.C. (1994). Preliminary evidence suggests that having obstructive sleep apnea may contribute to increased susceptibility to cardiovascular complications such as hypertension, cardiac arrhythmias, stroke, and myocardial infarction. Excessive daytime sleepiness is also a major complication.
Currently, the therapies used to treat obstructive sleep apnea include weight loss for the obese patient, Nasal-continuous positive Airway Pressure (a facemask used at night which produces a positive pressure within the upper airway), pharyngeal surgery and the administration of a variety of pharmacologic agents which have not been proven to be entirely successful. Chest 109 (5):1346-1358 (May 1996) entitled “Treatment of Obstructive Sleep Apnea”, a Review, hereby incorporated by reference. These agents include acetazolamide, medroxyprogesterone, opioid antagonists, nicotine, angiotensin-converting enzyme inhibitors and psychotropic agents (including those that prevent the reuptake of biogenic amines such as norepinephrine, dopamine and serotonin). Id. at 1353. Many of these pharmacological agents used also have a ventilatory depressant action (such as benzodiazepines) or other side effects such as urinary hesitancy and/or impotence in men (protriptyline) so that a new agent with fewer side effects is needed for the treatment of obstructive sleep apnea. Even though serotonin is a sleep-inducing agent and may be a ventilatory stimulant (Id. at 1354), 5HT2A receptor antagonists have been found useful in treating obstructive sleep apnea. See also Am. J. Respir Crit. Care Med (153) pp 776-786 (1996) where serotonin antagonists exacerbated sleep apnea produced in English bulldogs. But compare, Journal of Physiology (466) pp 367-382 (1993), where it is postulated that an excess of serotonin due to dysfunction of the serotonin biosynthesis mechanisms might set up conditions which favor obstructive apneas; European Journal of Pharmacology (259):71-74 (1994) further work on rat model with 5HT2 antagonist.
EP 1 262 197 discloses a method of treating sleep disorders including sleep apnea by administering to a patient in need of such a treatment a 5HT1A antagonist or an alpha-2-adrenergic antagonist in combination with an antidepressant such as serotonin reuptake inhibitor (SRI). Such a combination exhibits an improvement in efficacy.
U.S. Pat. No. 6,143,792 discloses that a specific 5HT2A receptor antagonist is useful in the treatment of the sleep apnea syndrome. Similarly, U.S. Pat. No. 6,576,670 discloses that a specific 5HT2A and 5HT2A/C receptor antagonist is useful in the treatment of snoring and upper airway high resistance syndrome.
U.S. Pat. No. 6,277,864 discloses that a specific 5HT2A receptor antagonist is useful in the treatment of a variety of sleep disorders.
A certain number of hypnotic agents, having various modes and acting duration, have also been developed over the years. For instance, a class of hypnotic agents have been developed which are long acting ones. Also, a class of short-acting hypnotic agents has also been developed. Generally, a short acting hypnotic agent acts mainly as a sleep inducer, i.e., the entry time into the sleep phase.
An example of a short acting hypnotic agent include without any limitation, zolpidem, which acts as a modulator of the GABA-A receptors. Zolpidem belongs to the imidazopyridine class and is administered orally in the form of an immediate-release tablet or in a galenic form allowing a delayed release. Zolpidem acts quickly, and is well absorbed with a 70% bioavailability. The average dosage, between 5 and 10 mg in a conventional formulation, induces a maximum plasma concentration which is reached between 0.5 and 3 hours of administration, the half life is short, with an average value of about 2.4 hours and an acting time of up to 6 hours.
Other examples of a short-acting hypnotic agent include without any limitation zaleplon, which belongs to the pyrazolopyrimidine class, zopiclone, eszopiclone, which belong to the cyclopyrrolone class, as well as their derivatives. Various other short acting hypnotic agents have also been developed including phenothiazines and benzodiazepines. Specific compounds belonging to these therapeutic classes include for example triazolam, brotizolam or alimemazine.
Long-acting hypnotic agents and/or sleep aids have also been developed. In the following it is understood that a long-acting hypnotic agent is referred to a compound or agent that is mainly a sleep inducer but may also be capable of improving sleep quality and/or maintenance in a patient. The “sleep aid” is a compound or agent that is mainly used to improve sleep quality and/or sleep maintenance in a patient, in particular the deep sleep phases. One such example of a sleep aid is an inhibitor of the 5HT2A receptors that acts without blockage of the dopamine, such as compounds of formula (I) as described herein.
Other long-acting hypnotic agents are, for example, temazepam, clonazepam, gaboxadol and pregabaline, a modulator of calcium ion, as well as their derivatives.
The hypnotic agents and/or the sleep aids described above improve sleep disorders, in particular, insomnia. However, whereas the short-acting hypnotic agents act mainly on the sleep-entry phase, the long-acting hypnotic agents act mainly on the sleep-entry phase but may also have a sleep maintenance component and sleep aids act rather on the deep-sleep phase, thus help to improve the overall quality of sleep in a patient.
Particularly, short acting GABAergic agonists such as zopiclone and eszopiclone provide benefits on sleep onset and sleep maintenance. However, optimal sleep maintenance effects may only be seen at doses that create a risk for next-day dysfunction, and which may raise unnecessary risks of memory and gait impairment, and of respiratory dysfunction. Therefore, an agent such as inhibitors of 5HT2A receptors that provides additional sleep maintenance effects, operating through a complementary mechanism, would be desired.
In addition, while zopiclone/eszopiclone do not have the negative effects on stage 3/4 sleep (Slow Wave Sleep; SWS) seen with benzodiazepines, they do not appear to significantly enhance SWS. These stages have been associated with the restorative activity of sleep, and hence enhancement of these stages, which are reduced in patients with sleep maintenance insomnia (at least as compared with young healthy volunteers), may provide improvement in daytime function, and possibly in addressing other disorders associated with aging and sleep deprivation (including increased adiposity, decreased lean body mass, and increased risk for diabetes mellitus) (Van Cauter et al., JAMA, 2000; 284:861-868).
The mechanism of serotonin 2A antagonism (5HT2A) may also facilitate circadian entrainment, an issue in older subjects who tend to have phase advancement and (especially in demented populations) a general disruption of rhythmicity of circadian processes.
It should also be noted that slow wave sleep (SWS) is associated with reduced risk of arousals and awakenings (Salzarulo et al., Sleep Research Online, 1999; 2:73-77). This may be particularly true in older subjects (Boselli et al., Sleep, 1998; 21:361-367). In addition, in older adult patients with insomnia, diminished SWS has been associated with cognitive impairments (Crenshaw & Edinger, Physiol. Behav., 1999; 66:485-492). A compound of formula (I) as disclosed herein has been found to increase SWS and decrease arousals and sleep stage shifts to wakefulness in patients with sleep maintenance insomnia.
Accordingly, it is an object of this invention to provide a combination, which allows combining the actions of the sleep aids and/or the long and short-acting hypnotic agents by improving the sleep quality and the respective effects of the short and long-acting hypnotic agents and/or sleep aids, without negative effect on the patient's waking-up phases.
Other objects and further scope of the applicability of the present invention will become apparent from the detailed description that follows.